Right ventricular (RV) contractile failure from acute RV pressure overload is an important cause of morbidity and mortality in conditions such as massive pulmonary embolism, hypoxic pulmonary vasoconstriction, and following cardiopulmonary bypass and cardiac transplantation.(1) RV failure is a leading cause of early mortality in patients undergoing cardiac transplantation, and often requires inotropic support or ventricular assist devices.
RV stroke volume is depressed during acute RV pressure overload, it had been assumed that this was a direct and reversible consequence of the increase in afterload, and did not reflect alteration in intrinsic RV contractile function. Thus, standard therapeutic strategies for management of RV contractile failure have concentrated almost exclusively on maneuvers to reduce RV afterload, such as pulmonary thromboendarterectomy in pulmonary embolism or use of inhaled nitric oxide following cardiopulmonary bypass or cardiac transplant.(2, 3) While there is no question that global RV ejection fraction improves with such therapeutic maneuvers, mortality in these conditions remains high. Whether the persistently high mortality in these conditions results entirely from incomplete treatment of the underlying condition, or is due in part to intrinsic dysfunction of the RV, has not been possible to determine because it is not generally possible to determine whether intrinsic RV function normalizes in clinical studies: typically there is no baseline assessment of RV function prior to development of acute pulmonary hypertension, and ordinary clinical indices of RV function, determined by echocardiography or nuclear scans, are not loading condition independent. Measurement of loading condition-independent indices of regional contractile function in humans is technically difficult, and may be impossible in critically ill patients. Thus, the question of whether acute RV pressure overload results in intrinsic RV contractile function has remained unresolved.
Clinical recovery from acute RV pressure overload is strongly influenced by success in alleviating whatever condition is responsible for pressure overload in the first place; but it is the RV contractile dysfunction, rather than the pressure overload per se, that directly contributes to morbidity and mortality. Thus, any factors that affect the development of or recovery from RV contractile dysfunction may necessarily play direct and important roles in ultimate clinical outcome. To date, there has been little investigative activity directed toward the mechanism of RV contractile dysfunction in this setting and thus there has been little investigation of potential therapeutic interventions to directly attenuate the development of RV contractile dysfunction from acute pressure overload.
Recently, studies have demonstrated that intrinsic RV contractile function remains significantly depressed following even a brief period of pressure overload, despite complete restoration of normal loading conditions. The severity of RV dysfunction following pressure overload is directly related to the level of RV free wall stress during pressure overload.(4) Such contractile dysfunction, while qualitatively similar to myocardial dysfunction of the left ventricle (LV) following ischemia-reperfusion, appears not to be due to ischemia of the RV.(5)
Thus, there is a current need for intervention in subjects with RV pressure overload directed toward restoration of RV contractile function.